Antimicrobial peptides (AMPs) have recently come to the forefront as potential antibiotic surrogates due to their robust killing activity against a wide-spectrum of bacterial species including drug-resistant strains. AMPs are genetically common molecules of innate immunity that have been discovered in single-cell and multicellular forms of life (Tossi et al. (2000) Biopolymers 55: 4-30; Diamond (2001) Biologist (London) 48: 209-212; Lehrer and Ganz (2002) Curr. Opin. Immunol. 14: 96-102; Brogden et al. (2003) Int. J. Antimicrob. Agents 22: 465-478). Although they can differ dramatically by peptide sequence and post-translational modification (linear, circular, etc), the majority of AMPs appear to kill bacteria by the disruption of lipid membranes, though the details of this mechanism appear to vary widely (Shai (2002) Biopolymers 66: 236-248; Brogden (2005) Nat. Rev. Microbiol. 3: 238-250). Previous observations have indicated the critical role of general hydrophobic and cationic character in AMP function, including the significant contribution of aromatic Trp and cationic Arg residues found in many AMPs (Chan et al. (2007) Biochim Biophys Acta. 51(4): 1351-1359; Wei et al. (2006) J. Bacteriol. 188: 328-334). Despite their small size (most AMPs are under 50 amino acids), secondary structure also appears to play an important role in activity. Certain linear AMPs can adopt an α-helical or β-strand confirmation upon interaction with hydrophobic environments (such as detergents or lipid vesicles) that mimic bacterial membranes, suggesting these conformational changes are necessary for antimicrobial function (Kiyota et al. (1996) Biochemistry 35: 13196-13204; Wei et al. (2006) J. Bacteriol. 188: 328-334; Wimmer et al. (2006) Biochemistry 45: 481-497). Additionally, the formation of a membrane-active a-helix (and other structures) appears to require an amphipathic spatial arrangement of residues, i.e., a gradient of hydrophobicity across the surface of the peptide (Kiyota et al. (1996) Biochemistry 35: 13196-13204; Shai (1999) Biochim Biophys Acta 1462: 55-70; Lee (2002) Curr Pharm Des 8: 795-813).
Previously, rational design of antimicrobial peptides has focused mainly on varying existing natural sequences, or developing novel peptides from large combinatorial libraries (Kiyota et al. (1996) Biochemistry 35: 13196-13204; Blondelle and Lohner (2000) Biopolymers 55: 74-87; Hong et al. (2001) Peptides 22: 1669-1674; Sawai et al. (2002) Protein Eng. 15: 225-232). These efforts have yielded valuable information on AMP structure-activity.
Streptococcus mutans, a common oral pathogen and the causative agent of dental caries, has persisted and even thrived on the tooth surface despite constant efforts to remove or eradicate them. New therapeutics against this organism are sorely needed, as S. mutans is a persistent colonizer of the tooth surface in the presence of dietary sugars and can remain in the oral microflora (known as dental plaque) despite dedicated mechanical removal (tooth brushing) and general antiseptic efforts (Keene and Shklair (1974) J. Dent. Res. 53: 1295).